PROJECT SUMMARY/ABSTRACT ? BLOOD CELL DEVELOPMENT AND FUNCTION PROGRAM The Blood Cell Development and Function (BCDF) Program is led by Balachandran and Wiest, and is comprised of 21 Primary and 6 Collaborating Members. Program funding is $7M (project direct costs) of which $6.1M is peer-reviewed and $1.9M is from the NCI. In addition to funded laboratory investigators, the Program includes 7 clinicians/clinical researchers, whose expertise and translational scientific interests are vital to inter- and intra-programmatic collaborations, and to accelerate translation of research findings to new insights and treatments for patients. Program members are highly productive and interactive: 11% of 305 publications are intra-programmatic, 17% are inter-programmatic, and 31% were published in high-impact journals. The scientific mission of the BCDF Program is to define how perturbations in control of cell fate decisions can lead to the development of blood cancers, to delineate how inflammation within a solid tumor can influence tumor progression, and to capitalize on the unique interactions between cells of the immune system and their targets to improve cancer immunotherapy. All members of this basic science program participate in cancer- relevant research, and over the past funding cycle, many basic science observations have advanced to translationally-focused studies. Highlighted examples underscore this ?basic-to-translation? trajectory. The mission of the Program is pursued through three inter-related themes: 1) to define processes that control hematopoiesis and assess their relevance to the etiology of hematologic malignancies (Development theme); 2) to define how the inflammatory response prevents or controls infections, and to apply that knowledge to how cancers develop and how they can be targeted (Inflammation theme); and 3) to explore how the action of immune cells and their soluble products (e.g., interferons) is controlled, with the ultimate aim of exploiting these insights to identify patients that are unresponsive to immunotherapy and to apply these insights to reverse immune exhaustion and restore vigorous anti-tumor immune responses. Specifically, BDCF investigators seek to identify non-responders prior to treatment and determine how to expand the number of patients who could benefit from such approaches (a developing Immune Effectors theme). Common scientific interests among investigators in this Program, coupled with new and extant inter- and intra-programmatic collaborations, enable synergies that interconnect these themes. Investigators within this Program benefit extensively from CCSG- supported Shared Resources, and rely heavily on the establishment and use of animal models. Consequently, many are major users of the Laboratory Animal Facility, including its zebrafish module, and the Transgenic Mouse Facility. Additional, cutting-edge technologies also further these themes, including multi-parametric flow cytometry, laser capture microdissection, next-generation sequencing, adoptive cellular transfers, genome editing with Zinc finger nucleases or CRISPR/Cas9, and copy number analysis, accomplished through the Cell Culture, Biological Imaging, Genomics, and Histopathology Facilities.